Opioid Painkillers Research Articles

Protective effect of dexmedetomidine against delayed bone healing caused by morphine via PI3K/Akt mediated Nrf2 antioxidant defense system.

As a class of analgesics, opioids are frequently used to treat both acute and chronic moderate to severe pain. Patients frequently receive opioid painkillers after orthopedic accidents or surgeries. Evidence suggests that opioid drug users have a 55.1% higher risk of fracture and poor bone repair than non-users of opioid drugs. The key pathogenic alterations in the incidence and progression of poor bone repair are over apoptosis and aging of osteoblasts due to the stress caused by oxidation. Dexmedetomidine (Dex) has been proven to protect against a variety of degenerative illnesses by reducing oxidative stress. However, nothing is known about how it affects bone repair. PI3K/Akt/Nrf2 pathway was detected by immunofluorescence and Western blot. SOD, CAT, JC-1, dihydroethidium and mitosox were used in the Oxidative Stress. Micro-CT, H&E and Masson's staining, immunohistochemically were performed to evaluate the therapeutic effects of DEX on calvarial defects in the morphine-induced rat model. We found that morphine-induced an imbalance in the metabolism and catabolism of primary rat Osteoblasts. However, these conditions could be inhibited by DEX treatment. In the meantime, DEX induced the expression of Nrf2-regulated antioxidant enzymes such as NQO1, HO-1, GCLm, GCLc, and TrxR1. DEX-mediated Nrf2 activation is linked to the PI3K/Akt signaling system. Furthermore, it has been established that intravenous DEX enhanced the growth of bone healing in a model of a surgically produced rat cranial lesion. This is the first description of the unique DEX mechanism acting as a Nrf2 activator against morphine-mediated oxidative harm, raising the possibility that the substance may be used to prevent bone defects.

Drug Stigma, Consumer Culture, and Corporate Power in the Opioid Crisis

Recent efforts to rethink drug-related stigma have been increasingly considering the power dimension of the concept, to show how stigma formations flow top-down from governments, as well as other political or corporate stakeholders, towards the powerless and marginalised. Stigma attaches itself to the individual and collective identities of the substance-using subject. But it equally alters the multiple lives of the substance. In the US opioid crisis of recent decades, big pharma companies could be seen lobbying the medical profession and harnessing their power to destigmatise opioid painkillers, as part of wider marketing and sales strategies. This has been subsequently linked with rising opioid-related fatalities and spiralling harms among some of the most vulnerable groups. This theoretical paper locates the object-stigma of drugs between the cultural confines of ‘limbic capitalism’ (the drive to seek pleasure and meaning through consumption) and ‘palliative capitalism’ (the drive to pathologise and medicate ills attributed to the individual, but not the system). It argues that stigma should be viewed as a dynamic force which, under the guise of consumer culture and the veil of scientific rationality, can be manipulated by business elites to shift meanings around pain, pleasure, and addiction, in ways that are potentially conducive to social harms.

The Imperative of Regulation: The Co-creation of a Medical and Non-medical US Opioid Crisis.

The ravaging COVID-19 pandemic has almost pushed into oblivion the fact that the United States is still struggling with an immense addiction crisis. Drug overdose deaths rose from 16,849 in 1999 to nearly 110000-of which an estimated 75,000 involved opioids-in 2022. On a yearly basis, the opioid casualty rate is higher than the combined number of victims of firearm violence and car accidents. The Covid-19 epidemic might have helped to worsen the addiction crisis by stimulating drug use among adolescents and diverting national attention to yet another public health crisis. In the past decade the sharpest increase in deaths occurred among those related to fentanyl and fentanyl analogs (illicitly manufactured, synthetic opioids of greater potency). In the first opioid crisis wave (1998-2010), opioid-related deaths were mainly associated with prescription opioids such as Oxycontin (oxycodone hydrochloride). The mass prescription of these narcotic drugs did anything but control the pervasive phenomenon of 'addiction on prescription' that played such an important role in the emergence and robustness of the US opioid crisis. Using a long-term drug lifecycle analytic approach in this article I will show how opioid producing pharmaceutical companies created a medical market for opioid painkillers. They thus fueled a consumer demand for potent opioid drugs that was eagerly capitalized on by criminal entrepreneurs and their international logistic networks. I will also point out the failure of US authorities to effectively respond to this crisis due to the gap between narcotic product regulation, regulation of marketing practices and the rise of a corporate dominated health care system. Ironically, this turned the most powerful geopolitical force in the war against drugs into its greatest victim. Due to formulary availability and regulatory barriers to accessibility European countries have been relatively protected against following suit the US opioid crisis.

Estrous cycle dependent expression of oxycodone conditioned reward in rats

Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.

Comparison of The Effects Between Different Opioid Receptors Painkiller

In searching for various kinds of painkillers and comparing the pharmaceutical effects of them, morphine and M6G, metadon, sufentanil are the most common and attractive among all the painkillers. The content below would mainly introduce the mechanism of opioid painkillers, which include the receptors and process of how opioids work, and these four drugs in their sources, effective dose, therapeutic effects and side effects. Except the same point of reliving pain, these drugs have different specialties and contraindication, so study them respectively and analogy them in different fields is essential to distinguish them and use them in different situations. Although the data from those literature is very convinced, there are still more studies need to be done to figure out more advanced drugs in the future.

Industry update, December 2022.

Industry update, December 2022.

Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design

We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.

Evonik and Allay Therapeutics developing polymer implants with additive for treating pain after knee surgery

On December 13, 2022, Evonik announced it had invested in the biopharmaceutical company Allay Therapeutics. The U.S.- and Singapore-based startup has developed an implant for treating pain after knee surgery. It is inserted directly into the knee and may relieve pain for up to three weeks - previous solutions work for a maximum of three days. The technology may promote the recovery process and make it possible to reduce or eliminate the administration of common opioid painkillers such as morphine or oxycodone. Biodegradable polymers from Evonik are the key to the success of this new type of pain therapy: they ensure that the active ingredients are delivered over a longer period.

Adductor canal block versus femoral nerve block for pain control after total knee arthroplasty: A systematic review and Meta-analysis.

Background:Femoral nerve block is a widely accepted nerve block method with evident reduction in consumption of opioid painkiller and minimization of the duration of hospital stay but may cause weakness of quadriceps muscle strength. Adductor canal block is another nerve block technique that attracts the attention of scientific community nowadays because of its possible superiority over Femoral nerve block regarding mobility and muscle strength.Methods:This is a systematic review and meta-analysis of 33 studies, aiming to compare femoral nerve block with adductor canal block following total knee arthroplasty regarding pain control and mobilization.Results:Adductor canal block showed better preservation of quadriceps muscle strength (MD = 0.28, 95% CI [0.11, 0.46], P = .002), and better mobilization up to 2 days postoperatively. However, no significant difference was found between the 2 interventions regarding pain control (MD = 0.06, 95% CI [−0.06, 0.17], P = .33) or opioid consumption (SMD = 0.08, 95% CI [−0.06, 0.22], P = .28) up to 2 days postoperatively. The better mobilization results of adductor canal block did not translate into a significant difference in the risk of falls or patients’ satisfaction; however, adductor canal block patients had less mean length of hospital stay than the patients with femoral nerve block.Conclusion:Both femoral nerve block and adductor canal block provide similar results regarding pain control and opioid consumption, however adductor canal block provides better preservation of quadriceps strength and mobilization, giving it more advantage over femoral nerve block.

Humanizing the Physician-Patient Relationship

Humanizing the Physician-Patient Relationship

Roles of GABAergic and Glutamatergic Prebötzinger Complex Circuits in Opioid‐Induced Respiratory Depression

Introduction. Opioids are widely prescribed analgesic medication but are highly addictive and can be lethal with overdose. Respiratory depression is the primary cause of death by opioid overdose, and it limits the ability to use opioid analgesics safely and effectively. Respiratory depression by opioids is mediated by the inhibition of neural circuits in the brainstem, such as the preBötzinger Complex (preBötC), a small region of the medulla involved in respiratory rhythm generation. The generation of respiratory rhythm requires the activation of excitatory and inhibitory neurons in the preBötC. Glutamate is a main excitatory neurotransmitter, and preBötC glutamatergic neurons are involved in generating respiratory rhythm. γ‐aminobutyric acid (GABA) is a main inhibitory neurotransmitter, and GABAergic neurons are found in the preBötC. Interestingly, GABAergic neurons often co‐express µ‐opioid receptors, and disinhibition of GABAergic neurons by opioid drugs is involved in opioid addiction and euphoria. Here, we aim to determine the roles of excitatory glutamatergic and inhibitory GABAergic neurons in opioid‐induced respiratory depression.MethodsTo control glutamatergic and GABAergic neurons, we expressed opsin channels in cells expressing the vesicular glutamate transporter 2 (vGLUT2) and the vesicular GABA transporter (vGAT), respectively. Using a cre‐lox recombination approach, we injected into the preBötC cre‐dependent adeno‐associated viruses to locally express the inhibitory archaerhodopsin or the excitatory channelrhodopsin in vGLUT2 or vGAT‐expressing cells. Following a 4‐week incubation period, we applied 554 nm or 470 nm lights through optical fibres focused onto the preBötC while recording diaphragm and genioglossal muscle activities in anesthetized mice. Following systemic injection of fentanyl (5µg/kg), we inhibited or activated glutamatergic or GABAergic cells, respectively.ResultsOur preliminary data indicate that inhibition of vGLUT2 cells severely depressed respiratory rate, mimicking the respiratory depression observed with the opioid fentanyl. We are currently performing optical inhibition of vGAT preBötC cells in anesthetized mice and determining their role in respiratory depression by fentanyl.DiscussionWe will identify the role of GABAergic and glutamatergic preBötC cells in coordinating respiratory rhythm in preBötC cells and whether GABAergic cells contribute to respiratory depression by opioid drugs. Understanding the role of the populations of cells involved in respiratory depression by opioid drugs is critical to identify new molecular targets to reduce respiratory depression and provide safe and reliable pain killers without the risks associated with opioid pain killers.

Behaviours of Patients Who Take Their Strong Opioids as Unmeasured ‘Sips’

ContextSome patients take their strong opioid painkillers as unmeasured sips. ObjectivesTo investigate how and why patients take their medication in this way. MethodsPatient receiving specialist palliative care who take their strong opioid painkillers as unmeasured sips were recruited. Measurement was made of the mass of two sips per patient and qualitative interviews using a topic guide were conducted. Interview transcripts were thematically analyzed using a phenomenological approach. ResultsOnly two of 16 patients were taking within 20% of the correct dose of their breakthrough liquid strong analgesia. Many varied the dose depending on the severity of the pain episode. Convenience, confusion about the correct dose, and issues with spoons were the other main reasons for people choosing to sip. ConclusionThis is the first published study exploring the behavior of patients who take their strong analgesia as unmeasured sips. Knowing that patients who sip are likely to be taking an incorrect dose, and the reasons behind sipping may help clinicians to help these patients to manage their pain better.

Effects of ‘doctor shopping’ behaviour on prescription of addictive drugs in Sweden

Free choice of health care providers is aimed to improve the quality of health care by increasing both access to it and the competition between providers. However, it may also give patients possibilities for doctor shopping (DS) behaviour, i.e., visiting different providers to receive illicit drug prescriptions. Abuse of prescribed addictive drugs is a growing problem worldwide and is associated with increased mortality, lower quality of life and other problems on both the individual and societal level. We study DS behaviour for three categories of addictive drugs – opioid painkillers, benzodiazepine anxiolytics, and z-hypnotic sleeping drugs, in the outpatient care sector in Västerbotten County, Sweden. Our dataset contains all drug prescriptions purchased by the residents of Västerbotten in the period from January 2014 to April 2016 (approximately 160,000 observations). To identify signs of addictive prescription drugs abuse by DS, we analyse overlapping prescriptions. We use ‘Defined Daily Doses' (DDDs), which is the average treatment dose of a specific drug per day for adults, as a proxy for the treatment duration. To control for medically legitimate overlaps, we compare overlapping prescriptions within a clinic with overlapping prescriptions between different clinics. Our empirical results suggest that there is a significant and positive relationship between the number of overlapping doses and the number of unique providers in the overlap. More specifically, we find that visiting different providers on average gives patients up to three additional DDDs per day. This is three times higher than the standard treatment dose. We discuss policy implications in the concluding discussion.

Epidemiological Characteristics of Sedative-Hypnotics and Opioid Painkillers at High-Frequency Exposure.

Drug poisoning has a high incidence and serious consequences in medical institutions; its epidemiological characteristics also directly affect the changes in national laws and policies and the implementation of local management policies. Chinese statistics on drug-related abnormal death cases generally come from judicial appraisal centers and medical units. However, due to differences in work content and professional restrictions, there are differences in information management forms, which makes it difficult for appraisers to conduct a professional and systematic analysis of drug-related cases. This article focuses on the analysis of epidemiological characteristics of sedative-hypnotics and opioid painkillers and their exposure patterns in cases of poisoning death by analyzing the annual report of the American Association of Poison Control Center, combined with the characteristics of drug exposure in China.

Alcohol trajectories and subsequent risk for opioid misuse in a cohort of urban adolescents

Background: The opioid epidemic is a public health emergency in the US. Alcohol is the most widely used addictive substance among all age groups; however, the contribution of different alcohol use trajectories throughout adolescence and young adulthood to the development of opioid misuse in young adulthood among urban minority youth has not been investigated. Methods: Data are from a study of 580 youth (85% African American, 67% low SES) residing in Baltimore City followed from ages 6–26. Alcohol trajectories were identified between ages 14 and 26 using group-based trajectory modeling. Opioid misuse was defined as using opioid painkillers without a prescription or using heroin between ages 19 and 26. Opioid misuse outcomes were also investigated separately. Logistic regression examined associations of alcohol trajectories with opioid misuse in young adulthood adjusting for socio-demographics, early use of tobacco and cannabis, neighborhood, and peer factors. Results: Six alcohol use trajectories were identified: Young adult increasing (21.4%), adult increasing (19.1%), abstaining (19.1%), experimenting (15.3%), adolescent increasing (14.8%), and adolescent limited (10.2%). In models fully adjusted for covariates, relative to the abstaining trajectory, the adolescent increasing trajectory was associated with an elevated risk of opioid misuse (aOR = 3.3, 95%CI = 1.4, 7.8) and prescription opioid misuse (aOR = 3.9, 95%CI = 1.4, 10.8) in young adulthood. Conclusions: Escalating alcohol use in adolescence and young adulthood is associated with an elevated risk of opioid misuse in young adulthood in a cohort of predominantly African American and socio-economically disadvantaged young people. Tailored interventions should target high levels of alcohol use during these developmental periods to reduce risk for opioid misuse among disadvantaged youth.

Analgesic choice in patients presenting to emergency department with cancer pain: a prospective study

Background. Acute onset pain is one of the common reasons for cancer patients to present to the emergency department. In our study, we compared painkillers used in cancer patients admitted to the emergency department with pain complaints and their effectiveness and the superiorities of these painkillers in pain relief and their superiorities over each other. Materials and methods. The pain scores of the patients were asked at the time of admission by showing a visual analogue scale. Before treatment, pain scores were recorded. The patients were divided into four different groups according to the type of given treatment: non-steroidal anti-inflammatory drugs; opioid painkillers; paracetamol; paracetamol and opioid therapy. After the treatment, we asked which painkiller written in the treatment form was administered to the patient and recorded the pain score. Results. It was observed that the median pain score before and after treatment of the patients in all painkiller groups differed statically. When the median scores before and after treatment were compared according to drug types, no difference was found between the decrease in pain scores (p = 0.956 and p = 0.705, respectively). It was concluded that the pre-treatment and post-treatment median pain scores of patients who are using non-steroid anti-inflammatory drugs and opioids at home did not differ statistically (p = 0.063). Conclusions. The use of non-steroidal anti-inflammatory drugs, paracetamol or opioids was not found to be superior to each other in patients with acute severe cancer pain.

Morphine attenuates neurotoxic effects of MPTP in zebrafish embryos by regulating oxidant/antioxidant balance and acetylcholinesterase activity

Parkinson's disease (PD) is one of the most common neurodegenerative diseases due to the loss of dopaminergic neurons in the midbrain in the substantia nigra. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic agent causing disruptions in mitochondria of dopaminergic neurons leading to impaired oxidant-antioxidant balance. Both zebrafish and zebrafish embryos are sensitive to MPTP. In zebrafish embryos, MPTP decreases the dopaminergic cells in the diencephalon by damaging dopaminergic neurons. Morphine is an opioid pain killer and a strong analgesic that is used to treat chronic pain. Until today morphine has been shown to regulate the survival or death of neurons and both protective and destructive effects of morphine have been reported in the central nervous system. This study aimed to evaluate the effects of morphine in MPTP-exposed zebrafish embryos. Developmental parameters were monitored and documented daily during embryonic development. Locomotor activity of zebrafish embryos at 96 h postfertilization (hpf) was determined. Acetylcholinesterase (AChE) activity and oxidant-antioxidant parameters were analyzed by biochemical methods. RT-PCR was used to evaluate bdnf, dj1, lrrk and pink1 expressions. Morphine treatment improved mortality and hatching rates, locomotor activity, AChE, and antioxidant enzyme activities as well as the expressions of bdnf, dj1, lrrk and pink1 in a dose-dependent manner that were altered by MPTP. Increased lipid peroxidation supports the role of morphine to induce autophagy to prevent PD-related pathologies. Our study provided important data on the possible molecular mechanism of the therapeutic effects of morphine in PD.

Pharmacists find purpose in end-of-life care

Pharmacists find purpose in end-of-life care

Opioid painkiller dependence in a sample of elderly medical inpatients.

Over the past few years, there has been a growing concern about prescription opioid misuse and dependence in the elderly. Our study aimed to investigate the prevalence of previous and current prescription opioid dependence among elderly medical inpatients recruited from a large German hospital. This cross-sectional study analyzed a cohort of inpatients aged 65 years and older who were assessed with a structured clinical interview. Levels of past and current dependence on opioids benzodiazepines, hypnotics, and non-opioid analgesics were assessed. Of 2108 elderly inpatients admitted to the hospital during a 6-month period, 400 fulfilled the inclusion criteria and agreed to participate to the survey. Among these 400 subjects, 43 (10.8%) presented with a dependence on opioid analgesics, including 41 with current dependence and 22 (51.2%) with a de novo condition. Addiction severity was considered mild in 65.1% of cases and severe in 11.6% of cases. Tilidine and oxycodone were the most typically reported molecules. Further research is warranted, to better understand the possible risk factors of prescription drug misuse, abuse, and addiction in this vulnerable population. Clinicians should be updated and informed regarding both prescription medication misuse potential and safe prescribing practices in the elderly.

Effect of electrothermal acupuncture on moderate to severe cancer pain with yin-cold stagnation: a randomized controlled trial

To observe the effectiveness and safety of electrothermal acupuncture therapy for patients of moderate to severe cancer pain with yin-cold stagnation. A total of 60 patients of moderate to severe cancer pain with yin-cold stagnation were randomized into an observation group and a control group, 30 cases in each one. In the control group, opioid painkillers (oxycodone hydrochloride prolonged-release tablet or morphine sulfate sustained-release tablet) were taken. On the basis of the control group, electrothermal acupuncture was applied at Guanyuan (CV 4), Qihai (CV 6), Zusanli (ST 36), Hegu (LI 4), Sanyinjiao (SP 6) in the observation group, 30 min each treatment, once a day for 5 days. Before and after treatment, the scores of pain numerical rating scale (NRS) and Karnofsky performance scale (KPS) were observed in the two groups. The pain remission rate, reduction of opioid painkillers and safety were compared. The variation of NRS scores in the observation group were larger than the control group 3, 5 days into treatment (P<0.01, P<0.05). The variation of KPS score in the observation group was larger than the control group after treatment (P<0.05). The pain remission rate was 100.0% (30/30) in the observation group, higher than 86.7% (26/30) in the control group (P<0.05). The reduction of opioid painkillers in the observation group was larger than the control group (P<0.01). There was no adverse reaction during the treatment in the two groups. On the basis of the conventional western medication for analgesia, electrothermal acupuncture could relieve pain, reduce the dose of opioid painkillers and improve the quality of life in patients of moderate to severe cancer pain with yin-cold stagnation, has a better safety.